Prediabetes: to treat or not to treat?

The incidence of diabetes is continuously increasing worldwide. Pre-diabetes (defined as impaired glucose tolerance, impaired fasting glucose or both) represents an intermediate state, which often progresses to overt diabetes within a few years. In addition, pre-diabetes may be associated with increased risk of microvascular and macrovascular complications. Thus, reverting a pre-diabetic state as well as preventing the development of diabetes represents enormous challenge for the clinician. Lifestyle modification in pre-diabetic individuals was found particularly effective in the prevention of diabetes. However, compliance to lifestyle modification measures can be a crucial problem in the everyday clinical practice, especially in developing countries. During the last decade many studies support the use of anti-diabetic treatment schemes in pre-diabetic subjects to be advantageous. The American Diabetes Prevention Program (DPP) as well as other minor studies and meta-analyses has convincingly demonstrated the efficacy of metformin in this patient group. In addition, results of the 10 year DPP follow up have recently been published, demonstrating the long term safety and sustainability of metformin treatment benefits in this population. In contrast to metformin, the evidence from the use of other anti-diabetic agents (thiazolidinediones, a-glucosidase inhibitors, incretin mimetics) in pre-diabetic individuals is rather inadequate and prospective data is further needed. Furthermore, large scale studies with hard clinical endpoints are needed to delineate the effect of pre-diabetes treatment on macro- and microvascular complications. In conclusion, several strategies of patient management, mainly lifestyle modification and pharmacological interventions can prevent diabetes development in subjects diagnosed with pre-diabetes or even revert pre-diabetic state. However, whether this biochemical improvement can be translated into actual clinical benefit remains to be established.     

Acknowledgement to Reviewers

All excellent peer reviewers who have volunteered their time and experience from April until June 2004 are listed below. We would like to express our great appreciation to them for their valuable contribution to the high quality of Acta Pharmacologica Sinica.     

Instructions to Authors

<正>本刊实行双盲审稿,利益回避和伦理审查制度(详见本刊投稿须知和《生物医学期刊投稿的统一要求》)。CPB follows a double-blind review procedure,the avoidance of conflicts of interest and ethical review system.     

Acknowledgement to Reviewers

AllexcellentpeerreviewerswhohavevolunteeredtheirtimeandexperiencefromJulyuntilSeptember2004arelistedbelow.WewouldliketoexpressourgreatappreciationtothemfortheirvaluablecontributiontothehighqualityofActaPharmacologicaSinicaChun－xueBAI(白春学)YaCAO(曹亚)Zhi－jieCHANG(常智杰)Yuan－zhongCHEN(陈元仲)Xiao－guangCHEN(陈晓光)Sheng－diCHEN(陈生弟)Ru－zhuCHEN(陈汝筑)Pei－huiCHEN(陈佩惠)Ming－daoCHEN(陈名道)Jian－pingCHEN(陈建平)Jian－guoCHEN(陈建国)Chong－hongCHEN(陈崇宏)YiCHE…     

What does it mean to want to quit?

INTRODUCTION AND AIMS: To report on the prevalence of attitudes and beliefs about the importance of wanting to quit and need for use of cessation assistance, that may act as barriers to quitting smoking and adopting cessation assistance. DESIGN AND METHODS: National telephone survey of 802 randomly selected adults (685 smokers, 117 recent quitters). RESULTS: Seventy per cent of smokers believed that 'wanting to quit' was both a necessary and sufficient condition for being able to quit. While only one-third of smokers believed that they were too addicted to be able to quit, only a quarter believed they could quit any time they want to. Belief that use of cessation assistance is a sign of weakness was endorsed by 35% of participants, and related to stage of change. DISCUSSION AND CONCLUSIONS: Beliefs about the importance of wanting to quit are commonly held. Many smokers appear to believe that a rational, unambivalent desire to quit is needed before it is worthwhile trying. Short-term impulses to act are not perceived as sufficient. The role of cessation assistance in helping smokers form a rational desire to quit appears to be poorly understood by the majority of smokers. There is a need to engender greater understanding of the potential value of cessation aids to smokers experiencing ambivalence about wanting to quit.     

Go to sleep

Go!来一次说走就走的旅行——是许多现代的年轻人希望拥有的潇洒。所谓千里之行始于足下，无论乘搭什么交通工具，始终是要靠自己的双脚去感受旅行的意义。我们的双脚让我们直立行走，解放了双手，从而才有了人类的文明。可惜进化是一个漫长的过程，我们的身体并非已经完全适应了直立行走，我们的双脚也不例外。直立让双脚承受比爬行时候超过1倍的压力，复杂的路面也让娇嫩的双脚无所适从，于是我们给双脚穿上了鞋。     

Acknowledgement to Reviewers

Allexcellentpeerreviewerswho havevolunteeredtheirtimeand experiencefromJanuary untilMarch2004arelisted below. Wewould liketoexpressourgreatappreciationtothemfortheirvaluablecontributiontothehighqualityofActaPharmacologicaSinica.GW　BOOZ Tian-hui　CHANG　(常天辉) Yuan-jian　LI　(李元建) Ye-ping　TIAN　(田野苹)Jeong-Hwa　BAEK Ji-qiang　CHEN　(陈季强) Chun　LIANG　(梁　　春) Hai　WANG　(汪　　海)Ai-xin　CHENG Ru-zhu　CH…     

How to unleash mitochondrial apoptotic blockades to kill cancers?

Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.     

Dyspepsia: how to manage and how to treat?

Recent guidelines for dyspepsia, defined as pain or discomfort centred in the upper abdomen, emphasize that in younger patients with no alarm features and not taking nonsteroidal anti-inflammatory drugs, testing for Helicobacter pylori and treatment of the infection if present is a standard of care. If H. pylori is not present, empirical management (e.g. acid suppression) is often prescribed. It is further recommended that if patients relapse or fail to respond to treatment then upper endoscopy be undertaken. However, these guidelines have become controversial for a number of reasons. Firstly, the prevalence of H. pylori infection is falling as is the incidence of peptic ulcer disease due to the infection. Idiopathic peptic ulcer disease is also being increasingly recognized. Furthermore, the cost-effectiveness of endoscoping treatment failures has been questioned, as the yield is low and patient management is usually not altered. Finally, it remains controversial whether the treatment of H. pylori infection in functional dyspepsia is of value, and two recent high quality meta-analyses have reached diametrically opposite conclusions. Alternative strategies, such as initially treating with acid suppression and then considering H. pylori infection in those who fail have been suggested, as has in low H. pylori prevalent regions the abandonment of a test-and-treat strategy. However, appropriate management trials of these alternative strategies in primary care are lacking. The management of patients with functional dyspepsia who fail initial antisecretory therapy is now difficult; prokinetics have fallen into some disrepute. Tricyclic antidepressants (at a low dose) may be useful in a subset, but adequate trials are lacking.     

Lamotrigine-associated rash: to rechallenge or not to rechallenge?

The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.     

What contributes to the sensitivity of microalgae to triclosan?

Differential sensitivities of microalgae to triclosan have been reported, which may have significant implications for environmental risk assessment of this widely used biocide. Therefore, the aim of this study was to derive a mechanistic understanding of varying microalgal sensitivity to this substance. The toxicity of triclosan was evaluated using microalgal systems varying in biological complexity, exposure time and systematic position (a synchronized culture of the chlorophyte Scenedesmus vacuolatus, a diatom Nitzschia palea cultivated in suspension as well as attached to surfaces and periphyton communities). The results revealed (1) differences in sensitivity of the selected microalgal systems of three orders of magnitude and (2) highest sensitivity of the chlorophyte to triclosan in the range of environmental concentrations. To investigate algal sensitivity to triclosan in more detail, bioavailability was considered by investigating suspended and attached living algae. Differences in the generation time (in comparison to test duration) of the species were addressed by evaluating and modeling concentration-time-effect relationships. However, varying sensitivities of the selected microalgal systems remained unexplained. Comparison of species-specific toxic responses to calculated effect concentrations, derived from quantitative relationships for narcosis and uncoupling mode-of-action, leads us to the conclusion that triclosan may address multiple target sites in different microalgal species.     

Does locomotor response to novelty in rats predict susceptibility to develop sensitization to cocaine and PHNO?

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 microg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.     

Is lorazepam-induced amnesia specific to the type of memory or to the task used to assess it?

Retrieval tasks can be classified along a continuum from conceptually driven (relying on the encoded meaning of the material) to data driven (relying on the perceptual record and surface features of the material). Since most explicit memory tests are conceptually driven and most implicit memory tests are data driven there has been considerable confounding of the memory system being assessed and the processing required by the retrieval task. The purpose of the present experiment was to investigate the effects of lorazepam on explicit memory, using both types of retrieval task. Lorazepam (2.5 mg) or matched placebo was administered to healthy volunteers and changes in subjective mood ratings and in performance in tests of memory were measured. Lorazepam made subjects significantly more drowsy, feeble, clumsy, muzzy, lethargic and mentally slow. Lorazepam significantly impaired recognition memory for slides, impaired the number of words remembered when the retrieval was cued by the first two letters and reduced the number of pictures remembered when retention was cued with picture fragments. Thus episodic memory was impaired whether the task used was conceptually driven (as in slide recognition) or data driven, as in the other two tasks. Analyses of covariance indicated that the memory impairments were independent of increased sedation, as assessed by self-ratings. In contrast to the deficits in episodic memory, there were no lorazepam-induced impairments in tests of semantic memory, whether this was measured in the conceptually driven task of category generation or in the data-driven task of wordstem completion.     

Subgroups: Time to Go Back to Basic Statistical Principles?

Exploratory subgroup analyses are an increasing source of controversy as part of the interpretation of the results of clinical trials. In this article, we review the major challenges of multiplicity, statistical methods available to assess consistency of effect, and the part appropriate design plays in mitigating the risk of false conclusions from subgroup analyses. We discuss the problems associated with using definitions of consistency based on effect sizes in specific subgroups. We argue that what is required is a return to basic statistical principles, including more use of modeling techniques.